Parkinson's disease is a progressive disease which is the second most common neurodegenerative disease. It is estimated that there are about 6.3 million Parkinson's disease patients globally, with about 1 out of 1,000 people. Although Parkinson's disease occurs common in the elderly, it occurs in young people too. Parkinson's disease is not easily distinguished from other diseases because the symptoms develop slowly. It is not easily detected in early stages and is accompanied by abnormal clinical symptoms such as tremor, stiffness, slowing of movement, postural instability, stooped posture, freezing of gait, depression, sleep disorder, dysuria, dementia, etc.
Although the cause of Parkinson's disease is not clear, it is known to be caused by deficiency in dopamine resulting from the loss of neurons that secrete the neurotransmitter dopamine in the brain. At present, the levodopa therapy of administering levodopa which is converted into dopamine in the body is commonly used. Although levodopa is the most effective therapeutic agent for Parkinson's disease, decreased drug efficacy or various motor disorders can occur during treatment. As alternative medications, COMT inhibitors, MAO-B inhibitors, etc., which maintain the concentration of dopamine in the brain by inhibiting the metabolism of dopamine, are used.
It is known that MAO-B not only plays an important role in dopamine metabolism in the brain but also inhibits damage to cranial nerve cells. Although there is no clear evidence that the MAO-B inhibitor actually delays the progress of Parkinson's disease, it is known that inhibition of MAO-B leads to inhibition of denaturation or destruction of dopaminergic neurons because it plays an important role in the onset of Parkinson's disease by MPTP or similar environmental toxicants. Also, there are evidences from animal and clinical tests that the MAO-B inhibitor has an effect of protecting the brain unlike other drugs.
Selegiline, which is approved as the most representative MAO-B inhibitor, is prescribed as a therapeutic agent for Parkinson's disease. However, it causes hepatotoxicity because it is metabolized to amphetamine and the irreversible inhibitor is accompanied by various side effects. Since rasagiline (Azilect) was first marketed in 2005 in Israel, it was marketed in about 50 countries including Europe, USA, etc. Azilect is free from amphetamine side effects and exhibits better efficacy than other dopaminergic drugs. However, although rasagiline also exhibits superior effect of inhibiting MAO-B like selegiline as an irreversible MAO-B inhibitor, it has a safety problem. Therefore, drugs that can effectively and reversibly inhibit the activity of MAO-B while solving the above-described disadvantages are being developed. However, no noticeable reversible inhibitor is available yet.
Obesity refers to a medical condition in which excess body fat has accumulated to the extent that it may have a negative effect on health. It is a condition in which excess energy has accumulated due to the difference in energy intake and energy expenditure. Obesity increases the likelihood of various diseases.
Because the previous studies on the hypothalamus regarding the regulation of food intake have been conducted centered on neurons as part of the brain, the understanding of the diet/obesity regulation by the brain has been limited. Therefore, study on glial cells (glia) which account for a greater part is necessary for a comprehensive understanding of the brain function. Recently, astrocytes which are the most abundant of the glial cells are spotlighted as cells that can activate or suppress nearby neurons by secreting various signaling molecules such as GABA (gamma-aminobutyric acid), glutamate, D-serine, ATP, etc. Astrocytes of the hypothalamus, which closely interact with POMC (pro-opiomelanocortin) neurons and express leptin receptors, can also contribute to leptin signaling.
In the hypothalamus, there exist two groups of POMC neurons, one that stimulates appetite and the other that stimulates energy consumption. Under normal situations, the astrocytes help the activation of nearby POMC neurons which stimulate energy consumption. However, in obesity, they turn to reactive astrocytes due to excessive leptin signals and putrescine is turned to GABA and secreted by MAO-B (monoamine oxidase B). In addition, the POMC neurons that stimulate energy consumption express GABAa receptors outside synapses including the a4, a5 and a6 subunits due to excessive leptin signals and are affected by the GABA secreted by the reactive astrocytes. As a result, the POMC neurons are inhibited and energy consumption is decreased, leading to accumulation of fats.
If MAO-B, which is the enzyme responsible for production of GABA, is inhibited, the production and secretion of GABA are inhibited and energy consumption is promoted as the POMC neurons are activated again. However, the POMC neurons that suppress appetite are not affected by GABA because they do not express GABAa receptors outside synapses. Therefore, the MAO-B inhibitors act on the POMC neurons which selectively excite energy consumption, thereby exhibiting an effect of treating obesity. However, most of the existing MAO-B inhibitors exhibit various side effects as irreversible inhibitors. Although drugs that can reversibly inhibit MAO-B are studied and developed for this reason, no noticeable reversible MAO-B inhibitor that can effectively act on obesity is available yet.